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Cancer Immunology, Immunotherapy

, Volume 67, Issue 5, pp 815–824 | Cite as

The multi-receptor inhibitor axitinib reverses tumor-induced immunosuppression and potentiates treatment with immune-modulatory antibodies in preclinical murine models

  • Heinz LäubliEmail author
  • Philipp Müller
  • Lucia D’Amico
  • Mélanie Buchi
  • Abhishek S. Kashyap
  • Alfred ZippeliusEmail author
Original Article

Abstract

Cancer immunotherapies have significantly improved the prognosis of cancer patients. Despite the clinical success of targeting inhibitory checkpoint receptors, including PD-1 and/or CTLA-4 on T cells, only a minority of patients derive benefit from these therapies. New strategies to improve cancer immunotherapy are therefore needed. Combination therapy of checkpoint inhibitors with targeted agents has promisingly shown to increase the efficacy of immunotherapy. Here, we analyzed the immunomodulatory effects of the multi-receptor tyrosine kinase inhibitor axitinib and its efficacy in combination with immunotherapies. In different syngeneic murine tumor models, axitinib showed therapeutic efficacy that was not only mediated by VEGF–VEGFR inhibition, but also through the induction of anti-cancer immunity. Mechanistically, a significant reduction of immune-suppressive cells, including a decrease of tumor-promoting mast cells and tumor-associated macrophages was observed upon axitinib treatment. Inhibition of mast cells by axitinib as well as their experimental depletion led to reduced tumor growth. Of note, treatment with axitinib led to an improved T cell response, while the latter was pivotal for the therapeutic efficacy. Combination with immune checkpoint inhibitors anti-PD-1 and anti-TIM-3 and/or agonistic engagement of the activating receptor CD137 resulted in a synergistic therapeutic efficacy. This demonstrates non-redundant immune activation induced by axitinib via modulation of myeloid and mast cells. These findings provide important mechanistic insights into axitinib-mediated anti-cancer immunity and provide rationale for clinical combinations of axitinib with different immunotherapeutic modalities.

Keywords

Cancer immunology Hematopoietic stem cell Mast cell Tumor-associated macrophage Tyrosine kinase inhibitor 

Abbreviations

BMMC

Bone marrow-derived mast cell

CCL2

CC-chemokine ligand 2

DT

Diphtheria toxin

FLT-3

Fms-like tyrosine kinase 3

mRCC

Metastatic renal cell carcinoma

PDGF

Platelet-derived growth factor

SCF

Stem cell factor

TAM

Tumor-associated macrophage

TKI

Tyrosine kinase inhibitor

VEGFR

Vascular endothelial growth factor receptor

WT

Wild type

Notes

Acknowledgements

We thank Masato Kubo for providing the Mas-TRECK mice for our experiment. We also thank Petra Herzig and Béatrice Dolder Schlienger for their technical support.

Author contributions

PM planned and performed experiments. MB performed experiments. HL and PM evaluated the data and designed the figures. LD’ and ASK analyzed the results. HL, PM, ASK, AZ wrote the manuscript.

Funding

This work was supported by funding from a Grant from the Swiss Cancer League (KFS-3394-02-2014 to Alfred Zippelius), the Cancer League Basel (Krebsliga beider Basel, to Philipp Müller and Heinz Läubli), the Huggenberger Stiftung (to Heinz Läubli) as well as the Goldschmidt-Jacobson Foundation (to Heinz Läubli).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Animal source

Mice were bought from Charles Rivers or bred in the animal facility of the Department of Biomedicine, University of Basel, Switzerland. Mas-TRECK mice were kindly provided by Masato Kubo. All animals were housed under specific pathogen-free conditions and in accordance with Swiss federal regulations (approved by the local ethical committee of Basel Stadt).

Supplementary material

262_2018_2136_MOESM1_ESM.pdf (2.3 mb)
Supplementary material 1 (PDF 2357 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Laboratory of Cancer Immunology, Department of BiomedicineUniversity Hospital and University of BaselBaselSwitzerland
  2. 2.Division of Oncology, Department of Internal MedicineUniversity Hospital BaselBaselSwitzerland
  3. 3.Department of Cancer Immunology and Immune ModulationBoehringer Ingelheim Pharma GmbH & Co. KGBiberach an der RissGermany

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